Dental caries is initiated by the demineralisation of hard tissue of the teeth usually by organic acids produced from fermentation of dietary sugar by dental plaque odontopathogenic bacteria. Dental caries is still a major public health problem. Further, restored tooth surfaces can be susceptible to further dental caries around the margins of the restoration. Even though the prevalence of dental caries has decreased through the use of fluoride in most developed countries, the disease remains a major public health problem. Dental erosion/corrosion is the loss of tooth mineral by dietary or regurgitated acids. Dental hypersensitivity is due to exposed dentinal tubules through loss of the protective mineralized layer, cementum and dental calculus is the unwanted accretion of calcium phosphate minerals on the tooth surface. All these conditions, dental caries, dental erosion/corrosion, dental hypersensitivity and dental calculus are therefore imbalances in the level of calcium phosphates.
Dental caries, dental erosion/corrosion and dental hypersensitivity can be treated with stabilized amorphous calcium phosphate (ACP) or stabilized amorphous calcium fluoride phosphate (ACFP) by providing bioavailable calcium and phosphate ions to replace the lost calcium phosphate mineral. Stabilized ACP and stabilised ACFP can also bind to the surface of dental calculus and prevent or reduce further accretion. Stabilized ACP and stabilized ACFP therefore can play a major role in preventing and treating oral diseases and other medical conditions.
Casein is present in milk in the form of micelles, which are believed to be roughly spherical particles with a radius of about 100 nm, dispersed in a continuous phase of water, salt, lactose and whey proteins (Schmidt, D. G. (1982) Dev. Dairy Chem. 1, 61-86). The casein micelles serve as a carrier of calcium phosphate providing a bioavailable source of calcium and phosphate ions for bone and teeth formation. The ability of casein micelles to maintain calcium and phosphate ions in a soluble and bioavailable state is retained by multiphosphorylated peptide fragments of the caseins known as the casein phosphopeptides (CPP). WO 98/40406 in the name of The University of Melbourne describes casein phosphopeptide-amorphous calcium phosphate complexes (CPP-ACP) and CPP-stabilised amorphous calcium fluoride phosphate complexes (CPP-ACFP) which have been produced at alkaline pH. Such complexes have been shown to prevent enamel demineralisation and promote remineralisation of enamel subsurface lesions in animal and human in situ caries models (Reynolds, 1998)
The CPP which are active in forming the complexes do so whether or not they are part of a full-length casein protein. Examples of active (CPP) that can be isolated by tryptic digestion of full length casein have been specified in U.S. Pat. No. 5,015,628 and include peptides Bos αs1-casein X-5P (f59-79) [1], Bos β-casein X-4P (f1-25) [2], Bos αs2-casein X-4P (f46-70) [3] and Bos αs2-casein X-4P (f1-21) [4] as follows:
[1]Gln59-Met-Glu-Ala-Glu-Ser(P)-Ile-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ile-Val-Pro- Asn-Ser(P)-Val-Glu-Gln-Lys79 αs1(59-79) [2]Arg1-Glu-Leu-Glu-Glu-Leu-Asn-Val-Pro-Gly-Glu-Ile-Val-Glu-Ser(P)-Leu- Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-Ile-Thr-Arg25 β(1-25) [3]Asn46-Ala-Asn-Glu-Glu-Glu-Tyr-Ser-Ile-Gly-Ser(P)-Ser(P)-Ser(P)-Glu-Glu- Ser(P)-Ala-Glu-Val-Ala-Thr-Glu-Glu-Val-Lye70 αs2(46-70) [4]Lys1-Asn-Thr-Met-Glu-His-Val-Ser(P)-Ser(P)-Ser(P)-Glu-Glu-Ser-Ile-Ile- Ser(P)-Gln-Glu-Thr-Tyr-Lys21 αs2(1-21)
It has now been found that peptide-stabilized soluble, basic forms of ACP and ACFP may also be produced in a medium having a pH of less than 7.0. Such complexes demonstrate a surprising level of activity to remineralise enamel subsurface lesions of teeth.
It will also be understood that the term “comprises” (or its grammatical variants) as used in this specification is equivalent to the term “includes” and may be used interchangeably and should not be taken as excluding the presence of other elements or features.